Schizophrenia is a complex disorder affecting behavior, perception and thinking. It is inadequately treated by existing medications. While many brain-based processes are thought to be disordered in schizophrenia, the neurotransmitter dopamine has been most strongly implicated. The brain makes dopamine from tyrosine, an amino acid present in the normal diet. For many years the supply of tyrosine to the brain was thought to be so ample that it did not limit dopamine production or release. Data from our own and other laboratories, however, show that tyrosine supply can affect dopamine. That is intriguing because one of the most consistent findings in schizophrenia has been abnormal transport of tyrosine across cell membranes, including those in the brain. This would lead to periods of abnormally high and abnormally low tyrosine in the brain. One hypothesis is that this abnormal tyrosine transport contributes to dopamine dysregulation. Our long-term objective is to better understand and treat disordered dopamine transmission in schizophrenia. Our short-term objective is to determine how tyrosine levels affect brain dopamine levels in the rat. Our specific aims are to raise and lower tyrosine levels in the brain, add conditions that are known to activate or dampen dopamine systems and then measure the net dopamine response. We will use in vivo microdialysis to sample the fluid between brain cells in awake animals and measure dopamine as well as noradrenaline and serotonin, other neurotransmitters that interact with dopamine. Tyrosine levels will be raised by administering tyrosine and lowered by giving a mixture of amino acids that limit entry of tyrosine into the brain. We will examine the prefrontal cortex, the striatum, the nucleus accumbens and hippocampus, regions implicated in schizophrenia. Drugs administered will include clozapine and haloperidol, medications used for the treatment of schizophrenia. Dopamine levels are regulated, among others, by the rate of dopamine production and of dopamine release; these turn are regulated by dopamine receptors. Based on earlier work we have developed an overall hypothesis linking the effects of tyrosine to the state of dopamine receptors, dopamine production and dopamine release. By testing different conditions we will support or refute elements of our hypothesis. 1. Lowering of brain tyrosine lowers dopamine levels only if certain dopamine receptors are inactivated. 2. Elevation of brain tyrosine levels raises dopamine levels only when dopamine production is increased and coupled to the dopamine levels. While the primary motivation for this proposal is to improve the treatment of schizophrenia, the resulting findings will contribute to our understanding of other conditions in which dopamine has been implicated. These include post-traumatic stress disorder, traumatic brain injury, addictive disorders and Parkinson's Disease, all of which are overrepresented in the VA Healthcare System and for which existing treatments are inadequate. PUBLIC HEALTH RELEVANCE: Project Narrative Schizophrenia is the most devastating of the serious mental illnesses. It affects behavior, perception, thinking and the ability to work and participate in meaningful relationships. Antipsychotic drugs are mainstays in the treatment of schizophrenia, but have very serious shortcomings. All the available medications carry the risk of significant side effects. These often lead patients to discontinue their medication and experience increased symptoms. In most patients, the medications have little if any impact on their ability to think and problem solve, skills which often limit reintegration into the community. Up to a third of patients with schizophrenia may continue to hear voices, experience paranoia and have difficulty in thinking and expressing themselves despite taking medications as prescribed. If recovery and reintegration into the community are goals, then currently available medications are highly unsatisfactory. The treatment of schizophrenia requires more VA resources than any other psychiatric illness. There are several reasons why this might be so. The veteran population is predominantly male and has a high prevalence of psychiatric co-morbidity. Furthermore, veterans with schizophrenia who are able to sustain full employment often seek their healthcare outside the VAMC. Since veterans with poor outcome schizophrenia are overrepresented in the VA Healthcare System, it is in the particular interest of the DVA to encourage a better understanding of the disorder and to develop better treatments There are multiple factors contributing to schizophrenia and many brain-based abnormalities that have been targeted for drug development. Of all of the abnormalities, those involving the brain neurotransmitter dopamine have been the most consistently demonstrated. Furthermore, all clinically available antipsychotic drugs target at least in part, the dopamine system. This is intriguing because the brain makes dopamine from the amino acid tyrosine. The movement of tyrosine across cell membranes is abnormal in schizophrenia. What this means is that the brain might at times have too much tyrosine and at other times too little tyrosine. The immediate goal of our proposal is to examine and understand how very high and very low brain tyrosine levels affect dopamine levels. This has several clinical applications. Correcting a dopamine imbalance - In schizophrenia there may not be enough dopamine in a region of the brain called the prefrontal cortex. Most scientists think that dopamine in the prefrontal cortex should be more sensitive to tyrosine than dopamine in other brain regions. With a good understanding of how tyrosine affects dopamine across brain regions, it should be possible to design an oral amino acid mixture that balances tyrosine and hence dopamine levels in schizophrenia. Oral amino acid mixtures are already being used to treat other conditions. Probing the brain - Clinical researchers have learned how to very briefly (for a few hours) lower the amount of tyrosine in the human brain. When tyrosine is lowered, the brain makes less dopamine. This affects how a person feels and how well he or she scores on tests of thinking and memory. This type of 'brain probe' has been used in over 26 studies over the last 6 years. It teaches us how dopamine works both in the healthy brain as well as in brain-based disorders. To properly understand such data, and to help us improve on this probe, researchers need to know precisely how tyrosine availability affects brain dopamine. Our proposal will provide that type of information. Studying other brain disorders - Dopamine has been implicated in many other brain disorders of particular importance to the VA Healthcare System. These include post-traumatic stress disorder, traumatic brain injury, addictive disorders and Parkinson's disease. Our data will fill in fundamental gaps in our understanding of how brain dopamine systems work. This will help researchers who study these other brain disorders.